Cloning a major gene for mouse adenovirus susceptibility

小鼠腺病毒易感性主基因的克隆

• 批准号: 7169213
• 负责人: Katherine R. Spindler
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169213
• 关键词: Acute Pneumonia; Adenovirus Infections; Adenoviruses; Alleles; Antiviral Agents; BALB/cJ Mouse; Backcrossings; Biological; Bone Marrow Transplantation; Brain; Candidate Disease Gene; Cessation of life; Child; Childhood; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 15; Cloning; Communicable Diseases; Congenic Strain; Developed Countries; Developing Countries; Disease; Disease susceptibility; Equilibrium; Exons; Gene Components; Gene Expression; Generations; Genes; Genetic; Genetic Epistasis; Genome; Genotype; Goals; Haplotypes; Immune; Immune response; Immune system; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Infection; Integration Host Factors; Introns; Life; Link; Maps; Minor; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Play; Polymorphic Microsatellite Marker; Positioning Attribute; Predisposition; Quantitative Trait Loci; Range; Recombinants; Recruitment Activity; Research; Research Personnel; Resistance; Resolution; Risk; Role; SJL/J Mouse; Single Nucleotide Polymorphism Map; Spleen; Study models; Susceptibility Gene; System; Testing; Tissues; Transgenes; Transgenic Mice; Transplant Recipients; Viral; Virus; Virus Diseases; base; bone; density; design; gene interaction; gene therapy; genetic linkage analysis; mortality; pathogen; programs; respiratory; tool; tumorigenesis; virus host interaction

DESCRIPTION (provided by applicant): Adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries, where they are a major cause of illness and death. 5-15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50-80%. However, little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Identification of such host factors will enable better design of antiviral and immune suppressive therapy and adenovirus-based gene therapy. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease, because it can be studied in the natural host and there are inbred strains with different susceptibilities to MAV-1. The objective of this proposal is to define and characterize the host gene(s) underlying a major quantitative trait locus (QTL) for MAV-1 susceptibility in inbred mice. The central hypothesis is that the major QTL on Chromosome 15 for MAV-1 susceptibility in SJL/J mice contains an immune system gene that is polymorphic in susceptible and resistant mice. Genetic mapping will be combined with candidate gene approaches in two specific aims. (1) The major QTL for susceptibility will be fine mapped using several complementary approaches. A high density of polymorphic markers will be used to genotype recombinant progeny backcross, intercross, and third-generation cross mice (recombinant progeny testing). An interval-specific congenic strain will be constructed in which the interval from susceptible SJL/J mice will be introgressed into the resistant BALB/cJ background. Additional inbred mouse strains will be tested to determine whether they share a genetic basis for susceptibility with the major QTL in SJL/J mice. If so they will be used for fine mapping, haplotype analysis, and candidate gene identification. (2) A list of 20-30 candidate genes for the Chromosome 15 QTL will be compared for sequence and gene expression differences between susceptible and resistant strains. A candidate gene will be identified and tested genetically by replacing it in a resistant strain with the susceptible allele. The project is expected to identify a previously undescribed interaction between host immune response and viral immune evasion, thus increasing our understanding of viral infections and mechanisms of host response to pathogens.

描述（由申请人提供）：腺病毒引起5-10%的儿童呼吸道疾病，并与发展中国家儿童的急性肺炎有关，是这些国家疾病和死亡的主要原因。5-15%的儿童骨髓移植患者发生腺病毒感染;发病率范围为50- 80%。然而，对腺病毒的发病机制，特别是宿主因素对疾病易感性的贡献知之甚少。这些宿主因子的鉴定将使得能够更好地设计抗病毒和免疫抑制治疗以及基于腺病毒的基因治疗。小鼠腺病毒1型（MAV-1）为研究感染性疾病的易感性提供了极好的模型，因为它可以在天然宿主中进行研究，并且存在对MAV-1具有不同易感性的近交系。本研究的目的是确定和鉴定近交系小鼠中MAV-1易感性的主要数量性状位点（QTL）的宿主基因。中心假设是SJL/J小鼠中MAV-1易感性的15号染色体上的主要QTL包含在易感和抗性小鼠中多态的免疫系统基因。遗传作图将结合候选基因的方法在两个特定的目标。(1)易感性的主要QTL将使用几种互补方法进行精细定位。将使用高密度多态性标记对重组后代回交、互交和第三代杂交小鼠进行基因分型（重组后代检测）。将构建间隔特异性同源品系，其中来自敏感SJL/J小鼠的间隔将渗入到抗性BALB/cJ背景中。将检测其他近交系小鼠品系，以确定它们是否与SJL/J小鼠中的主要QTL具有共同的易感性遗传基础。如果是这样，它们将用于精细绘图、单倍型分析和候选基因鉴定。(2)将比较15号染色体QTL的20-30个候选基因的列表，以确定易感株和抗性株之间的序列和基因表达差异。将通过用易感等位基因替换抗性菌株中的候选基因来鉴定和遗传测试候选基因。该项目预计将确定宿主免疫反应和病毒免疫逃避之间以前未描述的相互作用，从而增加我们对病毒感染和宿主对病原体反应机制的理解。